Despite the widespread availability of antiviral drugs the worldwide epidemic of genital herpes continues. HSV-2 increases the rate of acquisition of HIV-1 2-fold, the efficiency of transmission of HIV-1 5-7 fold, increases maternal to child transmission of HIV-1 and raises HIV plasma viral load by 0.5 logs. In the U.S. neonatal herpes now ranks as the infectious disease of greatest morbidity and mortality to the neonate in which no prevention strategy exists. Our recent studies have begun to provide the underlying biological mechanism for these epidemiological associations between HSV and HIV. The pace of reactivation and clearance of HSV infections is 10 fold "quicker" than previously appreciated;over 50% of mucosal HSV-2 reactivations last <12 hours, 85% of such reactivations are subclinical, and the frequency of reactivation may average at least 25 episodes yearly in immunocompetent persons. This P01 is focused on developing strategies to improve the clinical and public health morbidities of mucosal HSV infection. Project 1 "Mechanisms of Reactivation and Clearance of Mucosal HSV Infection" will explore the mechanisms that determine clearance of HSV from mucosal sites. A series of coordinated studies in HIV-, HIV+ and those undergoing solid organ and HSCT will define the relationship between anatomic site, gender, viral subtype, number of HSV-2 specific T cells in genital and mucosal skin and rates of viral reactivation and clearance. In addition, studies to define what dose and duration of anti-HSV therapy will reduce these short subclinical bursts of replication and their effect on HIV-1 suppression in plasma and genital mucosa will be conducted. Project 2. "Prevention of HSV Morbidity in Pregnancy and the Newborn" is directed at developing a more rationale strategy for reducing the morbidity of HSV infection in pregnancy by identifying and developing novel management strategies for the infant exposed to HSV at delivery. A sensitive and specific rapid PCR based assay that can detect HSV shedding in women at entry into the Labor and Delivery suite will be used to define the management strategy of infants exposed to HSV at delivery. Project 3 "Local Determinants of HSV-2 Shedding in Humans" will explore the relationship between viral reactivation and the frequency and number of plasmacytoid dendritic cells, chemokines utilization of locally infiltrating HSV specific T cells and the overall antiviral activity of T cell in lesional biopsies. The three scientific projects and supported by a Clinical Core, a Laboratory Core supporting the HSV and HIV assays, a Biostatistics and Data Management Core, and an Administrative Core supporting the human subjects and fiscal oversight. These studies will provide new understanding about the interactions between HSV and the peripheral mucosal immune system and lead to new management strategies for this infection. PROJECT 1: Mechanisms of Reactivation and Clearance of Mucosal HSV Infection Lawrence Corey, Project Leader PROJECT 1 DESCRIPTION (provided by applicant): Our studies in the last 2 years have shown that HSV-2 reactivation has both a more rapid and frequent pace of onset and clearance than previously appreciated;more than 40% of all HSV-2 reactivations last <6 hours;these short episodes of reactivation are characterized by the rapid release of 103 to 104 copies of HSV-2 DMA onto mucosal surfaces and accompanied by the rapid clearance of virus by the host. A similar pattern of reactivation appears to occur for oral-labial HSV infection. Host clearance of mucosal HSV varies considerably between individual from <0.3 logs of HSV DMA/hour to 2 logs/hour. Recent studies mapping CDS T cell responses in situ indicate that HSV-2 specific T cells in the periphery persist at the dermal-epidermal junction contiguous to neuronal endings and that the host immune responses can contain viral replication even before it causes mucosal ulcerations. This project is directed at characterizing the frequency of rapidly cleared mucosal HSV infections by anatomic site, gender, viral subtype (HSV-1 versus HSV-2), and degree of immunosuppression (immunocompetent patients, pregnant women, HIV positive patients on/off HAART, and patients post hematopoietic stem cell transplantation (HSCT). These studies will define the frequency in which rapidly cleared episodes occur in these patient populations. We will then enroll persons with rapid and slow clearance rates into mechanistic studies to define the association between clearance rate and the anatomic site and functional characteristics of HSV-2 specific CD8+ T-cells in skin. We will test the hypothesis that clearance rates of mucosal HSV reactivation will be inversely correlated with the presence of HSV-2 specific CD8+T cells in genital skin at the site of reactivation. Studies to define the functional characteristics of HSV- 2 specific cells that appear to participate in immune surveillance will also be performed. In addition, pilot studies to define if increasing doses of anti-HSV therapy will eliminate these short bursts of mucosal HSV reactivation and provide more optimal suppression of HSV-2 are proposed. Among HSV-2/HIV-1 co infected persons, we will define the temporal dynamics between HSV-2 reactivation and HIV-1 replication on mucosal surfaces using a newly developed, highly sensitive HIV-1 RNA assay and evaluate in sequential biopsy samples the role HSV-2 specific CD8+ T-cells play in resolution of HSV-2 in the HIV infected patient. We will test the hypothesis that dosing regimens that minimize sub clinical HSV-2 reactivation will produce more sustained reduction in HIV RNA among HIV co-infected persons with CD4 T-cell counts >400 cells/ml. Project 1 is designed to define and develop new strategies for controlling HSV-2 infection and identify high risk groups for which improved medical and public health management strategies can be initiated.